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| 9. |
- Sliz, E., et al.
(författare)
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Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
- 2023
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.
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| 10. |
- Tabassum, R, et al.
(författare)
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Genetic architecture of human plasma lipidome and its link to cardiovascular disease
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4329-
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Tidskriftsartikel (refereegranskat)abstract
- Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD.
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| 11. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 13. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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- Kurki, MI, et al.
(författare)
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FinnGen provides genetic insights from a well-phenotyped isolated population
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 613:7944, s. 508-
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Tidskriftsartikel (refereegranskat)abstract
- Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.
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| 17. |
- Lu, Yingchang, et al.
(författare)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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| 18. |
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| 19. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
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| 20. |
- Liu, C, et al.
(författare)
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A DNA methylation biomarker of alcohol consumption.
- 2018
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 23, s. 422-433
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Tidskriftsartikel (refereegranskat)abstract
- The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10(-7). Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10(-7). In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.
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| 21. |
- Shah, S, et al.
(författare)
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Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 163-
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Tidskriftsartikel (refereegranskat)abstract
- Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
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| 22. |
- Mousis, O., et al.
(författare)
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Scientific rationale for Saturn's in situ exploration
- 2014
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Ingår i: Planetary and Space Science. - : Elsevier BV. - 0032-0633 .- 1873-5088. ; 104, s. 29-47
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Tidskriftsartikel (refereegranskat)abstract
- Remote sensing observations meet some limitations when used to study the bulk atmospheric composition of the giant planets of our solar system. A remarkable example of the superiority of in situ probe measurements is illustrated by the exploration of Jupiter, where key measurements such as the determination of the noble gases' abundances and the precise measurement of the helium mixing ratio have only been made available through in situ measurements by the Galileo probe. This paper describes the main scientific goals to be addressed by the future in situ exploration of Saturn placing the Galileo probe exploration of Jupiter in a broader context and before the future probe exploration of the more remote ice giants. In situ exploration of Saturn's atmosphere addresses two broad themes that are discussed throughout this paper: first, the formation history of our solar system and second, the processes at play in planetary atmospheres. In this context, we detail the reasons why measurements of Saturn's bulk elemental and isotopic composition would place important constraints on the volatile reservoirs in the protosolar nebula. We also show that the in situ measurement of CO (or any other disequilibrium species that is depleted by reaction with water) in Saturn's upper troposphere may help constraining its bulk O/H ratio. We compare predictions of Jupiter and Saturn's bulk compositions from different formation scenarios, and highlight the key measurements required to distinguish competing theories to shed light on giant planet formation as a common process in planetary systems with potential applications to most extrasolar systems. In situ measurements of Saturn's stratospheric and tropospheric dynamics, chemistry and cloud-forming processes will provide access to phenomena unreachable to remote sensing studies. Different mission architectures are envisaged, which would benefit from strong international collaborations, all based on an entry probe that would descend through Saturn's stratosphere and troposphere under parachute down to a minimum of 10 bar of atmospheric pressure. We finally discuss the science payload required on a Saturn probe to match the measurement requirements.
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| 24. |
- de Pater, Imke, et al.
(författare)
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An Energetic Eruption With Associated SO 1.707 Micron Emissions at Io's Kanehekili Fluctus and a Brightening Event at Loki Patera Observed by JWST
- 2023
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Ingår i: Journal of Geophysical Research - Planets. - : American Geophysical Union (AGU). - 2169-9097 .- 2169-9100. ; 128:8
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Tidskriftsartikel (refereegranskat)abstract
- We observed Io with the James Webb Space Telescope (JWST) while the satellite was in eclipse, and detected thermal emission from several volcanoes. The data were taken as part of our JWST-ERS program #1373 on 15 November 2022. Kanehekili Fluctus was exceptionally bright, and Loki Patera had most likely entered a new brightening phase. Spectra were taken with NIRSpec/IFU at a resolving power R ≈ 2,700 between 1.65 and 5.3 µm. The spectra were matched by a combination of blackbody curves that showed that the highest temperature, ∼1,200 K, for Kanehekili Fluctus originated from an area ∼0.25 km2 in size, and for Loki Patera this high temperature was confined to an area of ∼0.06 km2. Lower temperatures, down to 300 K, cover areas of ∼2,000 km2 for Kanehekili Fluctus, and ∼5,000 km2 for Loki Patera. We further detected the a1Δ ⇒ X3Σ− 1.707 µm rovibronic forbidden SO emission band complex over the southern hemisphere, which peaked at the location of Kanehekili Fluctus. This is the first time this emission has been seen above an active volcano, and suggests that the origin of such emissions is ejection of SO molecules directly from the vent in an excited state, after having been equilibrated at temperatures of ∼1,500 K below the surface, as was previously hypothesized.
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| 27. |
- Lang, J. J. K., et al.
(författare)
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Unveiling and controlling the electronic structure of oxidized semiconductor surfaces: Crystalline oxidized InSb(100)(1 x 2)-O
- 2014
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Ingår i: Physical Review B (Condensed Matter and Materials Physics). - 1098-0121. ; 90:4
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Tidskriftsartikel (refereegranskat)abstract
- The exothermic nature of oxidation causes nearly all semiconductor applications in various fields like electronics, medicine, photonics, and sensor technology to acquire an oxidized semiconductor surface part during the application manufacturing. The significance of understanding and controlling the atomic scale properties of oxidized semiconductor surfaces is expected to increase even further with the development of nanoscale semiconductor crystals. The nature of oxidized semiconductor layers is, however, hard to predict and characterize as they are usually buried and amorphous. To shed light on these issues, we pursue a different approach based on oxidized III-V semiconductor layers that are crystalline. We present a comprehensive characterization of oxidized crystalline InSb(100)(1 x 2)-O layers by ab initio calculations, photoelectron spectroscopy, scanning tunneling microscopy, and spectroscopy, and demonstrate the electronic band structures of different oxidized phases of the semiconductor, which elucidate the previous contradictory semiconductor-oxidation effects. At 0.5 monolayer (ML) oxidation, oxygen atoms tend to occupy subsurface Sb sites, leading to metallic states in the semiconductor band gap, which arise from top dimers. When the oxidation is increased to the 1.0-2.0 ML concentration, oxygen occupies also interstitial sites, and the insulating band structure without gap states is stabilized with unusual occupied In dangling bonds. In contrast, the 2.5-3.0 ML oxide phases undergo significant changes toward a less ordered structure. The findings suggest a methodology for manipulating the electronic structure of oxidized semiconductor layers.
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| 30. |
- Kooner, Jaspal S, et al.
(författare)
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Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci.
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:10
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Tidskriftsartikel (refereegranskat)abstract
- We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10(-8) to P = 1.9 × 10(-11)). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10(-4)), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D.
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| 31. |
- Mendelson, Michael M., et al.
(författare)
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Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease : A Mendelian Randomization Approach
- 2017
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Ingår i: PLoS Medicine. - : PUBLIC LIBRARY SCIENCE. - 1549-1277 .- 1549-1676. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Background The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. Methods and Findings We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. Conclusions We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases.
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| 35. |
- Yildiz, B, et al.
(författare)
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Live well, die well - an international cohort study on experiences, concerns and preferences of patients in the last phase of life: the research protocol of the iLIVE study
- 2022
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Ingår i: BMJ OPEN. - : BMJ. - 2044-6055. ; 12:8
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Adequately addressing the needs of patients at the end of life and their relatives is pivotal in preventing unnecessary suffering and optimising their quality of life. The purpose of the iLIVE study is to contribute to high-quality personalised care at the end of life in different countries and cultures, by investigating the experiences, concerns, preferences and use of care of terminally ill patients and their families.Methods and analysisThe iLIVE study is an international cohort study in which patients with an estimated life expectancy of 6 months or less are followed up until they die. In total, 2200 patients will be included in 11 countries, that is, 200 per country. In addition, one relative per patient is invited to participate. All participants will be asked to fill in a questionnaire, at baseline and after 4 weeks. If a patient dies within 6 months of follow-up, the relative will be asked to fill in a post-bereavement questionnaire. Healthcare use in the last week of life will be evaluated as well; healthcare staff who attended the patient will be asked to fill in a brief questionnaire to evaluate the care that was provided. Qualitative interviews will be conducted with patients, relatives and healthcare professionals in all countries to gain more in-depth insights.Ethics and disseminationThe cohort study has been approved by ethics committees and the institutional review boards (IRBs) of participating institutes in all countries. Results will be disseminated through the project website, publications in scientific journals and at conferences. Within the project, there will be a working group focusing on enhancing the engagement of the community at large with the reality of death and dying.Trial registration numberNCT04271085.
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| 36. |
- Bonnert, M., et al.
(författare)
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Internet-Delivered Cognitive Behavior Therapy for Adolescents With Irritable Bowel Syndrome: A Randomized Controlled Trial
- 2017
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Ingår i: Am J Gastroenterol. - Stockholm : Ovid Technologies (Wolters Kluwer Health). - 0002-9270 .- 1572-0241. ; 112:1, s. 152-162
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Few treatments have been able to effectively manage pediatric irritable bowel syndrome (IBS). Internet-delivered cognitive behavior therapy (Internet-CBT) based on exposure for abdominal symptoms is effective for adult IBS. The objective of this study was to evaluate the efficacy of Internet-CBT based on behavioral exposure for adolescents with IBS. METHODS: Adolescents with IBS fulfilling the Rome III criteria were randomized to either Internet-CBT or a wait-list control. The Internet-CBT was a 10-week intervention where the main component was exposure to IBS symptoms by reduction of avoidance of abdominal symptoms and instead stepwise provocation of symptoms. The primary outcome was total score on Gastrointestinal Symptoms Rating Scale for IBS (GSRS-IBS). Secondary outcomes included adolescent- and parent-rated quality of life and parent-rated gastrointestinal symptoms. Difference between groups was assessed from pretreatment to posttreatment and the Internet-CBT group was also evaluated at 6 months after treatment completion. RESULTS: A total of 101 adolescents with IBS (13-17 years of age) were included in this study. Dropout rates were low (6%) and all randomized patients were included in intent-to-treat analyses based on mixed effects models. Analyses showed a significant larger pretreatment to posttreatment change on the primary outcome GSRS-IBS (B=-6.42, P=0.006, effect size Cohen's d=0.45, 95% confidence interval (0.12, 0.77)) and on almost all secondary outcomes for the Internet-CBT group compared with the control group. After 6 months, the results were stable or significantly improved. CONCLUSIONS: Internet-CBT based on exposure exercises for adolescents with IBS can effectively improve gastrointestinal symptoms and quality of life.
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| 37. |
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| 38. |
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| 39. |
- Heidegger, A., et al.
(författare)
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Development and inter-laboratory validation of the VISAGE enhanced tool for age estimation from semen using quantitative DNA methylation analysis
- 2022
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Ingår i: Forensic Science International: Genetics. - : Elsevier BV. - 1872-4973. ; 56
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Tidskriftsartikel (refereegranskat)abstract
- The analysis of DNA methylation has become an established method for chronological age estimation. This has triggered interest in the forensic community to develop new methods for age estimation from biological crime scene material. Various assays are available for age estimation from somatic tissues, the majority from blood. Age prediction from semen requires different DNA methylation markers and the only assays currently developed for forensic analysis are based on SNaPshot or pyrosequencing. Here, we describe a new assay using massively parallel sequencing to analyse 13 candidate CpG sites targeted in two multiplex PCRs. The assay has been validated by five consortium laboratories of the VISible Attributes through GEnomics (VISAGE) project within a collaborative exercise and was tested for reproducible quantification of DNA methylation levels and sensitivity with DNA methylation controls. Furthermore, DNA extracts and stains on Whatman FTA cards from two semen samples were used to evaluate concordance and mimic casework samples. Overall, the assay yielded high read depths (> 1000 reads) at all 13 marker positions. The methylation values obtained indicated robust quantification with an average standard deviation of 2.8% at the expected methylation level of 50% across the 13 markers and a good performance with 50 ng DNA input into bisulfite conversion. The absolute difference of quantifications from one participating laboratory to the mean quantifications of concordance and semen stains of remaining laboratories was approximately 1%. These results demonstrated the assay to be robust and suitable for age estimation from semen in forensic investigations. In addition to the 13-marker assay, a more streamlined protocol combining only five age markers in one multiplex PCR was developed. Preliminary results showed no substantial differences in DNA methylation quantification between the two assays, indicating its applicability with the VISAGE age model for semen developed with data from the complete 13-marker tool.
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| 40. |
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| 41. |
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| 42. |
- Martin-Almeida, M, et al.
(författare)
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Epigenome-Wide Association Studies of the Fractional Exhaled Nitric Oxide and Bronchodilator Drug Response in Moderate-to-Severe Pediatric Asthma
- 2023
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- Asthma is the most prevalent pediatric chronic disease. Bronchodilator drug response (BDR) and fractional exhaled nitric oxide (FeNO) are clinical biomarkers of asthma. Although DNA methylation (DNAm) contributes to asthma pathogenesis, the influence of DNAm on BDR and FeNO is scarcely investigated. This study aims to identify DNAm markers in whole blood associated either with BDR or FeNO in pediatric asthma. We analyzed 121 samples from children with moderate-to-severe asthma. The association of genome-wide DNAm with BDR and FeNO has been assessed using regression models, adjusting for age, sex, ancestry, and tissue heterogeneity. Cross-tissue validation was assessed in 50 nasal samples. Differentially methylated regions (DMRs) and enrichment in traits and biological pathways were assessed. A false discovery rate (FDR) < 0.1 and a genome-wide significance threshold of p < 9 × 10−8 were used to control for false-positive results. The CpG cg12835256 (PLA2G12A) was genome-wide associated with FeNO in blood samples (coefficient= −0.015, p = 2.53 × 10−9) and nominally associated in nasal samples (coefficient = −0.015, p = 0.045). Additionally, three CpGs were suggestively associated with BDR (FDR < 0.1). We identified 12 and four DMRs associated with FeNO and BDR (FDR < 0.05), respectively. An enrichment in allergic and inflammatory processes, smoking, and aging was observed. We reported novel associations of DNAm markers associated with BDR and FeNO enriched in asthma-related processes.
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| 43. |
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| 44. |
- Riedel, M., et al.
(författare)
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Improving e-Science with Interoperability of the e-Infrastructures EGEE and DEISA
- 2008
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Ingår i: MIPRO 2008 - 31st International Convention Proceedings. - 9789532330366 ; , s. 225-231
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Konferensbidrag (refereegranskat)abstract
- In the last couple of years, many e-Science infrastructures have begun to offer production services to e- Scientists with an increasing number of applications that require access to different kinds of computational resources. Within Europe two rather different multi-national e-Science infrastructures evolved over time namely Distributed European Infrastructure for Supercomputing Applications (DEISA) and Enabling Grids for E-SciencE (EGEE). DEISA provides access to massively parallel systems such as supercomputers that are well suited for scientific applications that require many interactions between their typically high numbers of CPUs. EGEE on the other hand provides access to a world-wide Grid of university clusters and PC pools that are well suited for farming applications that require less or even no interactions between the distributed CPUs. While DEISA uses the HPC-driven Grid technology UNICORE, EGEE is based on the gLite Grid middleware optimized for farming jobs. Both have less adoption of open standards and therefore both systems are technically non-interoperable, which means that no e-Scientist can easily leverage the DEISA and EGEE infrastructure with one suitable client environment for scientific applications. This paper argues that future interoperability of such large e-Science infrastructures is required to improve e-Science in general and to increase the real scientific impact of world-wide Grids in particular. We discuss the interoperability achieved by the OMII-Europe project that fundamentally improved the interoperability between UNICORE and gLite by using open standards. We also outline one specific scientific scenario of the WISDOM initiative that actually benefits from the recently established interoperability.
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| 46. |
- Abdel-Aziz, MI, et al.
(författare)
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A System Pharmacology Multi-Omics Approach toward Uncontrolled Pediatric Asthma
- 2021
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Ingår i: Journal of personalized medicine. - : MDPI AG. - 2075-4426. ; 11:6
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Tidskriftsartikel (refereegranskat)abstract
- There is a clinical need to identify children with poor asthma control as early as possible, to optimize treatment and/or to find therapeutic alternatives. Here, we present the “Systems Pharmacology Approach to Uncontrolled Pediatric Asthma” (SysPharmPediA) study, which aims to establish a pediatric cohort of moderate-to-severe uncontrolled and controlled patients with asthma, to investigate pathophysiological mechanisms underlying uncontrolled moderate-to-severe asthma in children on maintenance treatment, using a multi-omics systems medicine approach. In this multicenter observational case–control study, moderate-to-severe asthmatic children (age; 6–17 years) were included from four European countries (Netherlands, Germany, Spain, and Slovenia). Subjects were classified based on asthma control and number of exacerbations. Demographics, current and past patient/family history, and clinical characteristics were collected. In addition, systems-wide omics layers, including epi(genomics), transcriptomics, microbiome, proteomics, and metabolomics were evaluated from multiple samples. In all, 145 children were included in this cohort, 91 with uncontrolled (median age = 12 years, 43% females) and 54 with controlled asthma (median age = 11.7 years, 37% females). The two groups did not show statistically significant differences in age, sex, and body mass index z-score distribution. Comprehensive information and diverse noninvasive biosampling procedures for various omics analyses will provide the opportunity to delineate underlying pathophysiological mechanisms of moderate-to-severe uncontrolled pediatric asthma. This eventually might reveal novel biomarkers, which could potentially be used for noninvasive personalized diagnostics and/or treatment.
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| 49. |
- Anttila, V., et al.
(författare)
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Direct intramyocardial injection of VEGF mRNA in patients undergoing coronary artery bypass grafting
- 2023
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Ingår i: Molecular Therapy. - : Elsevier BV. - 1525-0016. ; 31:3, s. 866-874
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Tidskriftsartikel (refereegranskat)abstract
- Vascular endothelial growth factor A (VEGF-A) has therapeutic cardiovascular effects, but delivery challenges have impeded clinical development. We report the first clinical study of naked mRNA encoding VEGF-A (AZD8601) injected into the human heart. EPICCURE (ClinicalTrials.gov: NCT03370887) was a randomized, double-blind study of AZD8601 in patients with left ventricular ejection fraction (LVEF) 30%–50% who were undergoing elective coronary artery bypass surgery. Thirty epicardial injections of AZD8601 (total 3 mg) or placebo in citrate-buffered saline were targeted to ischemic but viable myocardial regions mapped using quantitative [15O]-water positron emission tomography. Seven patients received AZD8601 and four received placebo and were followed for 6 months. There were no deaths or treatment-related serious adverse events and no AZD8601-associated infections, immune reactions, or arrhythmias. Exploratory outcomes indicated potential improvement in LVEF, Kansas City Cardiomyopathy Questionnaire scores, and N-terminal pro-B-type natriuretic peptide levels, but the study is limited in size, and significant efficacy conclusions are not possible from the dataset. Naked mRNA without lipid encapsulation may provide a safe delivery platform for introducing genetic material to cardiac muscle, but further studies are needed to confirm efficacy and safety in a larger patient pool. © 2022
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